PROJECT SUMMARY The immune system promotes adipose tissue homeostasis through a tightly orchestrated network of pro- and anti-inflammatory signaling events. The Th2 cytokines interleukin-13 (IL-13) and IL-4 temper inflammation and promote insulin sensitivity through the alternative activation of resident macrophages. IL-13 and IL-4 have also been reported to regulate the development and activation of thermogenic beige adipocytes through canonical and non-canonical mechanisms that have not been fully elucidated. Upon activation, beige adipocytes rapidly take up glucose and fatty acids to fuel heat production, making them a potential target for the treatment of obesity and type 2 diabetes. Data from our lab and others indicate that in mice, Th2 cytokines directly act on adipocyte progenitor cells to promote the development of beige cells, a cell population that rapidly dissipates after 4 weeks of age. The source of beige cells in adult animals remains an unanswered question. The molecular mechanism through which Th2 cytokines induce beige adipogenesis is also unclear. Preliminary data indicate that activation of this program in early post-natal development appears to be crucial for the establishment of an inducible pool of beige adipocytes that persists into adulthood. We hypothesize IL-13-IL-13Ra signaling plays a key role in this process. The current research plan will utilize two conditional Il13ra1 knockout models to define the roles of IL- 13 in preadipocytes and mature adipocytes, respectively. In vitro models, including primary preadipocytes and immortalized inguinal preadipocyte cell lines from wild-type and Il13ra1-/- mice will be used to investigate the mechanism by which the IL-13Ra1/STAT6/PPARg signaling axis promotes beige adipogenesis. Investigation of these regulatory mechanisms in preadipocytes will clarify existing discrepancies, characterize unexplored mediators of thermogenesis, and may inform the development of more targeted therapies for obesity and type 2 diabetes. The proposed research will be conducted within the Department of Molecular Metabolism at the Harvard T.H. Chan School of Public Health. The department specializes in the study of metabolism and is equipped with both the facilities and expertise to facilitate the successful completion of this work. Harvard Medical School core facilities and faculty with expertise in adipocyte biology will serve as a further source of support for this work. The goal of the fellowship training is to publish the research findings and present results at a scientific conference by the end of the funding period.